Ifosfamide, an oxazaphosphorine with broad-spectrum clinical activity, is a key component of many front-line protocols for the treatment of both solid tumors and hematologic malignancies. Ifosfamide is not active in its own right; it requires P-450-mediated oxidative metabolism in the liver to express cytotoxicity. Despite its broad-spectrum activity, ifosfamide has several major shortcomings that limit its utility. Prominent among these is organ-specific toxicities, particularly, urotoxicity, nephrotoxicity and neurotoxicity. These toxicities, which are associated with the 'unwanted metabolites' of ifosfamide, principally acrolein and chloroacetaldehyde, seriously limit optimal drug administration. A second shortcoming of ifosfamide is drug resistance. Although several resistance mechanisms have been identified, elevated aldehyde dehydrogenase (ALDH) levels plays a prominent role in many murine and human tumor cell lines. A further clinical limitation of ifosfamide is that it can not be used for regional chemotherapy because of the need for hepatic activation. The goal of this proposal is to develop new prodrugs of isophosphoramide mustard (IPM), the active metabolite of ifosfamide, that will avoid many of the toxicities caused by the 'unwanted metabolites' of ifosfamide. In this application, two new classes of IPM prodrugs that do not require oxidative activation are proposed. The new analogs proposed may be enzymatically convert to IPM under biological conditions. Accordingly, the new analogs should not cause many of the organ toxicities that have limited the clinical application of ifosfamide. The proposed prodrugs do not generate aldehyde intermediates, and therefore, are not susceptible to ALDH-mediated detoxification. Finally, since the prodrugs are activated in all tissues, they could be useful for regional chemotherapy as well as for the systemic management of patients with cancer. The principal investigator proposes to synthesize a number of prodrugs and study their (a) biotransformations in biologic tissues, (b) cytotoxicities against tumor cell and drug-resistant variants, (c) antitumor activities against experimental tumors and human tumor xenografts in mice, (d) organ toxicities in the mouse, and (e) antitumor efficacy compared with IPM and melphalan when administered by limb perfusion in a rat sarcoma tumor model.